title: Bleeding response induced by anti-thrombotic doses of a phosphoinositide 3-kinase (PI3K)-β inhibitor in mice.
abstract: BACKGROUND
  Published evidence suggests that phosphoinositide 3 kinase-β (PI3K-β) plays an important role in platelet aggregation and shear activation. TGX-221 is a selective PI3K-β inhibitor with a good separation of anti-thrombotic efficacy and bleeding (therapeutic index) in rats. Our goal was to further evaluate potential of a PI3K-β inhibitor as an anti-thrombotic agent by determining the therapeutic index in another species and efficacy model. Reported effects of TGX-221 in rats were also confirmed.
  
  
  METHODS
  TGX-221 (0.3 + 0.3, 1 + 1, 3 + 3 mg/kg + mg/kg/hr, i.v.) or vehicle was given to mice starting 15 min prior to FeCl(3) arterial thrombosis (AT), tail or kidney bleeding time (BT) procedures.
  
  
  RESULTS
  Integrated blood flow over 30 min (%baseline mean ± SEM) improved (p < 0.05) with TGX-221 doses 1 + 1 (49 ± 13.9%) and 3+3 (88 ± 10.6%) versus 0.3 + 0.3 (10 ± 0.8%) and vehicle (10 ± 0.6%). Vascular patency (non-occluded/total arteries) improved (p < 0.01) with TGX-221 doses of 3 + 3 (7/8), but not 0.3 + 0.3 (0/8) or 1 + 1 (4/8) versus vehicle (0/8). Tail BT (sec) increased (p < 0.05) with TGX-221 doses of 3 + 3 (median 1560) and 1 + 1 (1305) versus vehicle (225). Mean renal BT (sec) increased (p < 0.05) in all TGX-221 groups (3 + 3: 510 + 26; 1 + 1: 478 + 41; 0.3 + 0.3: 246 + 37) versus vehicle (123 + 9). For comparison, a reference agent, aspirin (30 mpk, i.p.) increased tail BT 1.9X and renal BT 2.6X.
  
  
  CONCLUSIONS
  The novel finding of a clear impact on hemostasis by TGX-221 was demonstrated by increased bleeding in two models in mice at anti-thrombotic doses. The results suggest a narrower therapeutic index for this PI3K-β inhibitor than previously recognized, at least for this species.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. eileen.bird@bms.com
authors.forename: J Eileen
authors.initials: JE
authors.lastname: Bird
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Smith
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bostwick
authors.forename: Petia
authors.initials: P
authors.lastname: Shipkova
authors.forename: William A
authors.initials: WA
authors.lastname: Schumacher
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects*; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007668:Kidney / Q000098:blood supply; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000097:blood; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones / Q000097:blood / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013623:Tail / Q000098:blood supply
chemical_list: D005343:Fibrinolytic Agents; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones; C504718:TGX 221